Compounds known to have antifolate activity are well recognized as chemotherapeutic agents for the treatment of cancer. In particular, compounds in the folic acid family have various activities at the enzymatic level as they inhibit such enzymes as dehydrofolate reductase, folate polyglutamate synthetase, glycinamide ribonucleotide formyltransferase and thymidylate synthetase.
European publication No. 0434426 (“EP '426”) discloses a class of 4-hydroxypyrrolo[2,3-d]pyrimidine-L-glutamic acid derivatives, and states that these compounds have antifolate activity and anti-tumor effect. See EP '426, p. 2, 11. 33-56. Among them are hydrate crystalline forms of disodium pemetrexed.
Pemetrexed disodium salt heptahydrate is marketed by Eli Lilly and Company under the trade name ALIMTA® as a sterile lyophilized powder for intravenous administration. This member of the folic acid family has been approved for treatment of malignal pleural mesothelioma and for second-line treatment of non small cell lung cancer. See Physicians' Desk Reference, 60th ed., pp. 1722-1728 (2006).
International PCT publication WO 01/14379 discloses hydrate crystalline disodium pemetrexed.
The preparation of the commercial lyophilized or formulated lyophilized pemetrexed disodium is disclosed in U.S. Pat. No. 7,138,521. This pemetrexed disodium is prepared from N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]L-glutamic acid diethylester p-toluenesulfonic acid salt, which is saponified at a pH of between 2.5 to 3.5 to give N-[4-[2(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (“pemetrexed diacid”), of the following Formula II:
The pemetrexed diacid is isolated as a wet cake and then combined with 2 to 3 equivalents of sodium hydroxide at a pH of between 7 and 9. The resulting pemetrexed disodium heptahydrate is then isolated from the reaction mixture by precipitation using acetone. The isolated pemetrexed disodium heptahydrate is then used to prepare the pharmaceutical composition.
Pemetrexed diacid and its preparation is believed to have been described for the first time in U.S. Pat. No. 5,344,932.
Formation and isolation of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid from a mixture of water and ethanol having a pH of 2.5-3.5 is disclosed in U.S. Pat. No. 7,138,521. A similar isolation is disclosed in C. J. Barnett, et al., “A Practical Synthesis of Multitargeted Antifolate LY231514,” Organic Process Research & Development, 3(3): 184-188 (1999).
Formation and isolation of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid from an aqueous solution having a pH of 5 is disclosed in U.S. Pat. No. 5,416,211.
Formation and isolation of pemetrexed diacid from an aqueous solution of the p-toluenesulfonic acid salt of the corresponding dialkyl ester compound by addition of sodium hydroxide and adjusting the pH to 2.8-3.1 is disclosed in U.S. Pat. No. 6,262,262.
The occurrence of different crystal forms (polymorphism) is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of solids having distinct physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint and NMR spectrum. The differences in the physical properties of polymorphs result from the orientation and intermolecular interactions of adjacent molecules (complexes) in the bulk solid.
Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous and/or disadvantageous physical properties compared to other forms in the polymorph family. One of the most important physical properties of pharmaceutical polymorphs is their solubility in aqueous solution, which may influence the bioavailability of the drug.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance that can be identified unequivocally by X-ray spectroscopy. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by solid state 13C NMR spectrometry and infrared spectroscopy.
The discovery of new polymorphic forms of pemetrexed diacid provides a new opportunity to improve the performance of the synthesis of the active pharmaceutical ingredient (API), pemetrexed disodium, by producing crystalline forms of pemetrexed diacid having improved characteristics, such as flowability, and solubility. Thus, there is a need in the art for polymorphic forms of pemetrexed diacid.